The Antepenultimate Truth

A copy of a letter just sent to New Scientist. They've printed two of mine already--both on the interpretation of quantum mechanics, a topic yet to appear here.

Jessica Smith of the UK Alzheimer’s Society points out the need to “tease out the difference between those with type 2 diabetes who develop Alzheimer’s and those that don’t” (6 December, p 6). I believe a hugely important clue to Alzheimer’s susceptibility was discovered by the Nun Study of Aging and Alzheimer’s Disease, but its practical significance has gone unrecognized.

The Nun Study compared age-22 autobiographical essays written by those who did and did not go on to develop the disease, and discovered a remarkable difference in what the Study analysts have characterized as linguistic density and complexity (high levels being protective). That difference, however, can be better characterized by the “intuitive / sensing” trait dichotomy of Jung’s personality theory; the nuns at risk had characteristically produced mere lists of facts about themselves, while those who proved to be immune featured a “complexity of interrelated ideas.” (This interpretation was doubtlessly missed because the commercialization of Jung’s theory as the Meyers-Briggs Type Indicator has made it unfashionable, and because it is mistakenly believed to be necessarily in conflict with the better-established Big Five model, when it in fact attempts to describe a deeper level of traits).

In a term paper for a Harvard graduate seminar in 2001, I presented a wealth of evidence to argue that this trait (better called “interpretive / empirical”) is fundamental, and is mediated by the basal forebrain cholinergic system, whose paradigmatic role is the inhibition of the brain’s default associative spread. (The paper received an A grade from Professor Mark Baxter, now of the Icahn School of Medicine at Mount Sinai, and one of the pioneering researchers on the role of acetylcholine in regulating attention.) The cholinergic system is well known to innervate the pyramidal cells that in Alzheimer’s are destroyed by beta-amyloid plaques, and to suffer catastrophic damage itself, beginning in the early stages of the disease.

My hypothesis in 2001 was that interpretive types, with their innate low levels of cholinergic regulation, were somehow immune to the disease process. The apparent mechanism is now clear. In pyramidal cells, amyloid precursor protein (APP) has a well-established regulation by acetylcholine. Deficits in this regulation are known to increase the production of beta-amyloid, which in turn is neurotoxic to the cholinergic cells. This is one of the destructive feedback loops characteristic of the disease process, and it may underlie the extraordinarily elevated disease risk of individuals with Down syndrome. Trisomy 21 produces an abnormal surplus of APP—seemingly too much for ordinary levels of acetylcholine to regulate properly.

It would therefore seem to be impossible for interpretive types, with their low innate levels of cholingeric innervation, to have anything but correspondingly low levels of APP in the cells involved in the disease process. These levels are apparently so low that aberrant production of beta-amyloid, regardless of originating factor, can never cross the threshold where any of the components of the disease process can begin. (While the function of APP is far from fully characterized, it is believed to be involved in synapse formation, which could be part of a mechanism for coordinating normal APP levels with their regulatory innervation.)

This hypothesis is attractive, because the interpretive / empirical trait is immensely easier to test for than the linguistic density and complexity that it mediates. One simply asks for endorsement of a statement such as “things remind me of other things all the time”; a 4 or 5 answer on a 5-point Likert scale indicates a low or extremely low disease susceptibility. (That particular question has achieved highly significant correlations with predicted behavioral responses in a preliminary version of my own trait instrument.) Verifying this would be a great boon to ongoing research. Researchers who wish a copy of the 2001 paper may contact me by commenting on the [copy / longer version] of this letter at ericmvan.com.